Longitudinal bone growth occurs at the growth plate, a thin layer of cartilage which lies near the ends of long bones and vertebrae. At the growth plate, endochondral ossification results in the formation of new trabecular bone. However, longitudinal bone growth requires the formation not only of trabecular bone (spongy bone found in the interior of long bones) but also cortical bone (dense bone found at the periphery of long bones). The mechanisms responsible for longitudinal growth of the bone cortex have not previously been identified. We have now demonstrated that longitudinal growth of the cortex occurs by coalescence of trabecular bone formed at the periphery of the growth plate. In this region of coalescing trabeculae close to the periosteum, osteoblast surface (the fraction of bone surface covered by osteoblasts) was increased compared to trabeculae farther from the periosteum. Osteoclast surface did not differ. In vitro, osteoblast proliferation was increased when cultured in the presence of periosteum or periosteum-conditioned medium. Insertion of permeable or impermeable membranes between periosteum and spongiosa did not prevent cortex formation. Based on these studies we conclude that metaphyseal cortical bone is formed by coalescence of endochondral trabecular bone. This coalescence is associated with increased osteoblast surface in the peripheral trabecular bone. The increased osteoblast surface could be due to inductive effects of periosteum; periosteum stimulates osteoblast proliferation in vitro, but is not required for metaphyseal cortical bone formation in vivo. We have found evidence that longitudinal bone growth slows with age because the growth plate chondrocytes have a finite proliferative capacity that is gradually exhausted. Estrogen accelerates this process, causing early termination of linear growth and early epiphyseal fusion. Consistent with this hypothesis, we have found that estrogen receptors -alpha and -beta are both expressed in growth plate chondrocytes throughout postnatal development. We have recently completed a clinical study of girls with precocious puberty. In these girls, the precocious puberty caused the growth plates to be exposed to high levels of estrogen. We found clinical evidence that proliferative exhausion of the growth plate chondrocytes in these girls had been accelerated and that the severity of the acceleration correlated with the severity of the estrogen exposure. These findings are consistent with our hypothesis that estrogen accelerates proliferative exhaustion in human growth plate chondrocytes.